HCV infects nearly 3% of the world population and is often referred as a silent epidemic. It is a leading cause of liver cirrhosis and cancer, and many infected are not aware of the infection until signs of liver malfunction develop. Although significant progress has been made recently in virus treatment, there is no vaccine to stop virus transmission. The central hypothesis for this Program Project is that a vaccine inducing potent broadly neutralizing antibody responses will be effective in preventing HCV transmission in high risk population despite of the virus genetic diversity. Project 1 will study the antibody response in humans who have been vaccinated by the E1E2 antigen in a previous Phase 1 Clinical Trial, and in humans who have been infected by HCV. In parallel, antibody and B cell responses in preclinical animal models vaccinated with E1E2 antigens will be studied and compared to the human studies. This research project will produce a comprehensive set of data on the antibodies, B cell lineages, and HCV immune epitopes to guide rational vaccine design effort. This project will be directed by Dr. Mansun Law. Project 2 will capitalize on the recent structural information on HCV broadly neutralizing epitopes and advances in computational protein design to develop epitope-focused immunogens and their particle forms as vaccine antigens to elicit neutralizing antibody responses to the conserved immune epitopes. This project will be led by Dr. Jiang Zhu. The two projects will utilize antibody and viral reagents developed in the Law lab, which will be managed by an Admin Core. The PIs will also assist each other in their projects with their complementary skills. Dr. Law will provide expertise on HCV, virus neutralizing antibodies, and animal models for immunization. Dr. Zhu will provide expertise in next-generation sequencing of B cell repertoire and immunogen design. The Admin Core will facilitate their communication and productivity by taking care of all administrative duties as well as coordinating research activities including sample organization, shipment and storage between the labs and the collaborative sites. The combined expertise and effort of the team, guided by the valuable advice from internal and external experts, provide a solid foundation to accelerate the discovery of promising HCV vaccine candidates.